Biology subjects

Jorgensen, M.

Publications and source records attributed to Jorgensen, M..

6 recordsLinked to original sources

bioRxiv2024

Cancer-independent, second somatic NF1 mutation of normal tissues in neurofibromatosis type 1

INTRODUCTIONCancer predisposition syndromes mediated by recessive cancer genes generate tumours via somatic variants (second hits) in the unaffected allele. Second hits may or may not be sufficient for neoplastic transformation. Here, we performed whole genome and exome sequencing on 479 tissue biopsies from a child with neurofibromatosis type 1, a multi-system cancer-predisposing syndrome mediated by constitutive monoallelic NF1 inactivation. We identified multiple independent NF1 driver variants in histologically normal tissues, but not in 610 biopsies from two non-predisposed children. We corroborated this finding using targeted duplex sequencing, including a further nine adults with the same syndrome. Overall, truncating NF1 mutations were under positive selection in normal tissues from individuals with neurofibromatosis type 1. We demonstrate that normal tissues in neurofibromatosis type 1 commonly harbour second hits in NF1, the extent and pattern of which may underpin the syndromes cancer phenotype.

cancer biology↗

bioRxiv2024

Surviving under Ice: Insights into gene-expression changes during ice encasement in timothy (Phleum pratense L.)

The predicted increase in frequency and duration of winter warming episodes (WWEs) at the higher northern latitudes is expected to negatively impact the forage production in this region. The formation of non-permeable ice cover due to WWEs creates hypoxic or anoxic conditions for plants leading to severe winter damages. Knowledge about molecular mechanisms underlying various winter stresses is crucial to develop cultivars with better winter survival under changing climatic conditions. In the current study, we aimed at identifying genes involved in ice encasement stress responses by RNAseq in the perennial forage grass timothy (Phleum pratense L.) and study gene expression differentiation due to field survival using cultivars with diverse genetic backgrounds. The LD50 estimates varied across cultivars and material. The expression of ethylene-responsive transcription factors, alcohol dehydrogenase, pyruvate decarboxylase, sucrose synthase, dehydrins, and heat shock proteins were highly upregulated under ice encasement conditions. Functional analysis of differentially expressed genes revealed that the upregulated genes were involved in glycolysis, pyruvate metabolism, carbon metabolism, and biosynthesis of amino acids while genes involved in photosynthesis, phenylpropanoid biosynthesis and flavonoid biosynthesis pathways were downregulated. The results from the current study indicate a substantial overlap of ice encasement stress responses with those of hypoxia and freezing stresses. In addition, the potential strategies leading to higher ice encasement tolerance of timothy are outlined. Furthermore, differences in gene expression between field survivors and the original plant material, and differences between ice encasement responses of northern-adapted and southern-adapted cultivars are briefly discussed.

plant biology↗

bioRxiv2023

Normal Uterine Fibroblast Are Reprogramed into Ovarian Cancer-Associated Fibroblasts by Ovarian Tumor-derived Conditioned Media

Cancer-associated fibroblasts (CAFs) are key contributors to ovarian cancer (OC) progression and therapeutic resistance through dysregulation of the extracellular matrix (ECM). CAFs are a heterogenous population derived from different cell types through activation and reprogramming. Current studies rely on uncharacterized heterogenous primary CAFs or normal fibroblasts that fail to recapitulate CAF-like tumor behavior. Here, we present a translatable-based approach for the reprogramming of normal uterine fibroblasts into ovarian CAFs using ovarian tumor-derived conditioned media to establish two well-characterized ovarian conditioned CAF lines. Phenotypic and functional characterization demonstrated that the conditioned CAFs expressed a CAF-like phenotype, strengthened proliferation, secretory, contractility, and ECM remodeling properties when compared to resting normal fibroblasts, consistent with an activated fibroblast status. Moreover, conditioned CAFs significantly enhanced drug resistance and tumor progression and resembled a CAF-like subtype associated with worse prognosis. The present study provides a reproducible, cost-effective, and clinically relevant protocol to reprogram normal fibroblasts into CAFs using tumor-derived conditioned media. Using these resources, further development of therapeutics that possess potentiality and specificity towards CAF-mediated chemoresistance in OC are further warranted.

cancer biology↗

bioRxiv2021

Anatomical Structures, Cell Types, and Biomarkers Tables Plus 3D Reference Organs in Support of a Human Reference Atlas

1.This paper reviews efforts across 16 international consortia to construct human anatomical structures, cell types, and biomarkers (ASCT+B) tables and three-dimensional reference organs in support of a Human Reference Atlas. We detail the ontological descriptions and spatial three-dimensional anatomical representations together with user interfaces that support the registration and exploration of human tissue data. Four use cases are presented to demonstrate the utility of ASCT+B tables for advancing biomedical research and improving health.

cell biology↗

bioRxiv2020

The mutational landscape of human somatic and germline cells

During the course of a lifetime normal human cells accumulate mutations. Here, using multiple samples from the same individuals we compared the mutational landscape in 29 anatomical structures from soma and the germline. Two ubiquitous mutational signatures, SBS1 and SBS5/40, accounted for the majority of acquired mutations in most cell types but their absolute and relative contributions varied substantially. SBS18, potentially reflecting oxidative damage, and several additional signatures attributed to exogenous and endogenous exposures contributed mutations to subsets of cell types. The mutation rate was lowest in spermatogonia, the stem cell from which sperm are generated and from which most genetic variation in the human population is thought to originate. This was due to low rates of ubiquitous mutation processes and may be partially attributable to a low cell division rate of basal spermatogonia. The results provide important insights into how mutational processes affect the soma and germline.

genomics↗

bioRxiv2020

ACE2 and SARS-CoV-2 Expression in the Normal and COVID-19 Pancreas

Diabetes is associated with increased mortality from Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2). Given literature suggesting a potential association between SARS-CoV-2 infection and diabetes induction, we examined pancreatic expression of the key molecule for SARS-CoV-2 infection of cells, angiotensin-converting enzyme-2 (ACE2). Specifically, we analyzed five public scRNAseq pancreas datasets and performed fluorescence in situ hybridization, Western blotting, and immunolocalization for ACE2 with extensive reagent validation on normal human pancreatic tissues across the lifespan, as well as those from coronavirus disease 2019 (COVID-19) patients. These in silico and ex vivo analyses demonstrated pancreatic expression of ACE2 is prominent in pancreatic ductal epithelium and the microvasculature, with rare endocrine cell expression of this molecule. Pancreata from COVID-19 patients demonstrated multiple thrombotic lesions with SARS-CoV-2 nucleocapsid protein expression primarily limited to ducts. SARS-CoV-2 infection of pancreatic endocrine cells, via ACE2, appears an unlikely central pathogenic feature of COVID-19 as it relates to diabetes.

pathology↗